The term "orthomolecular" was first coined in a 1967 letter[4] by Nobel Prize winner Linus Pauling and later elaborated on in a 1968 paper[5] on micronutrients and psychiatry to express the idea of "the right molecules in the right amounts" (ortho is Greek for right[6]). In this paper, Pauling indicated that the right molecules are "substances that are normally present in the human body."

Some megavitamin therapies can be classified as components of orthomolecular medicine. Orthomolecular practitioners often recommend levels beyond the Recommended Daily Allowance, especially in the prescription of vitamin C megadosage. Megavitamin therapies have become relatively popular, with a survey in 2002 finding that approximately one in twenty-five US adults use high doses of vitamins as a form of therapy,[14] with this being particularly common in people diagnosed with cancer.[15]

Nutrients may be useful in preventing and treating some illnesses,[16][17] but the conclusions of medical research are that the broad claims of disease treatment by advocates of orthomolecular medicine are unsubstantiated by the available evidence.[18][19][16] The American Medical Association stated in 1997 that "much of the dietary intervention stressed by alternative healers is prudent and reasonable", but described as a "myth" the idea that "most diseases are caused by faulty diets and can be prevented by nutritional interventions".[20] Critics have described some aspects of orthomolecular medicine as food faddism or even quackery.[21][22][23] Research on nutrient supplementation in general suggests that some nutritional supplements might be beneficial, and that others might be harmful.[24][25][26]

As a discipline focused upon using nutrients to treat illness, orthomolecular medicine practitioners trace the origin of the field back to the discovery of vitamins in the early 20th century,[27] although the word "orthomolecular" was coined by Linus Pauling in 1967. Thus orthomolecular practitioners lay claim to figures who preceded later controversies and labels, and perhaps would have rejected the controversial treatments which were later called orthomolecular medicine. Practitioners claim these figures were orthomolecular because of their emphasis on the role of nutrition in treating disease. In a paper on the history of orthomolecular medicine, Menolascino[28] notes that there were several eras in the use of nutrition to treat disease. After the discovery of nutrients at the dawn of the 20th century, some doctors began to think that vitamins could cure many ailments, and nutrition was incorporated into the medical curriculum. Supplements became widely available. As spectacular results were not forthcoming, in the 1950s and 1960s medical science slowly became disillusioned with nutrition and cut it from the standard curriculum,[28] just as orthomolecular medicine was being founded. Orthomolecular medicine highlights some figures from these early years as their founders.

In the 1930s Max Gerson (1881 - 1959) developed Gerson therapy, a specific diet which he claimed could treat many diseases. In 1933, Wilfred and Evan Shute began to use vitamin E in attempts to treat heart disease.[29] Some of the concepts frequently utilized in orthomolecular medicine, such as individual biochemical variation,[8]inborn error of metabolism,[30][28][31] and exogeneous supply of essential substances in therapy[32] debuted in scientific and medical papers early in the 20th century. Orthomolecular megavitamin therapies, such as with tocopherols and ascorbates,[33] date back to the 1930s.

In 1948, William McCormick theorized that vitamin C deficiency played an important role in many diseases, and began to use large doses in patients.[34] In the 1950s, American doctor Frederick Klenner also experimented with the use of vitamin C megadosage as a therapy for a wide range of illnesses, most notably polio, and authored 28 research papers during his career.[35][36] McCormick and Klenner influenced biochemist Irwin Stone, who extensively researched vitamin C and received the first patent for its commercial use. Stone found that all living beings have vitamin C. Further, nearly all vertebrates produce vitamin C, and produce much more when stressed. Some primates, including humans, do not produce vitamin C, and Stone claimed that this was due to a genetic defect which he called hypoascorbemia.[37] Based on a rat's production of vitamin C, a 70 kg human would produce between 1.8 and 4 grams of vitamin C, and a stressed human up to 15.2 grams.[38] This contrasts with the current Dietary Reference Intake, which maintains that 90 mg is adequate, and increases that to 120 mg if pregnant.[39] Based on the levels of vitamin C in other vertebrates, Stone believed that ascorbate was not a trace vitamin but was required in humans in large daily amounts. He produced four papers between 1965 and 1967 to back up this assertion.[40][41][42][43] In 1966 Stone met Linus Pauling and sparked Pauling's interest in vitamin C.[44]

In 1967, Linus Pauling introduced the expression orthomolecular medicine to describe one aspect of medicine,[4] and the term "orthomolecular therapy", as published in Science in 1968, to express the idea of the right molecules in the right amounts.[5] Pauling subsequently defined "orthomolecular medicine" as "the treatment of disease by the provision of the optimum molecular environment, especially the optimum concentrations of substances normally present in the human body" or as "the preservation of good health and the treatment of disease by varying the concentrations in the human body of substances that are normally present in the body and are required for health."[49]

Orthomolecular medicine has diversified since its beginnings in1968, but the term orthomolecular is still associated with Pauling's advocacy of vitamin C megadosage for optimal health. Partly for this reason, detractors of orthomolecular medicine have described the practice entirely in terms of megadose nutrient therapy. Barrie R. Cassileth, a widely quoted critic of Pauling's ideas, asserts: "In 1968, the Nobel-prize-winning scientist Linus Pauling coined the term "orthomolecular" to describe the treatment of disease with large quantities of nutrients."[50] In this way, criticism of orthomolecular medicine has, to a large extent, been confused with much older medical traditions of high-dose vitamin therapies, such as earlier "megadose" usages of retinol and ergocalciferol or synthetic pharmaceutical analogues, such as menadione.[51][52][53] Such definitions of orthomolecular therapy are not synonymous with Pauling's definition. Interest in vitamin C has been renewed, beginning with the discovery that intravenous vitamin C can achieve plasma concentrations up to 70-fold higher than oral vitamin C.[54] A 2005 paper in the Proceedings for the National Academy of Sciences noted that vitamin C selectively killed cancer cells in vitro. This paper noted that, although the original observational studies of vitamin C were based on intravenous administration, the subsequent double-blind placebo-controlled studies used oral ascorbate.[55] In 2007, the researchers demonstrated how vitamin C in vivo could possibly kill cancer cells.[56] A recent historical study of the past ten years has found three patients whose tumors shrank after receiving intravenous vitamin C along with other alternative and conventional treatments. The authors of the study claimed that the case studies "only significant treatment" for these patients was vitamin C.[57][58] However, this is far from conclusive, and studies are currently planned at the McGill University.[59]

In 2008 researchers gave vitamin C intravenously to mice with human derived cancers and observed slower tumor growth and may less metastasis.[60] The authors suggested that the ascorbate was acting as a pro-oxidant and generating hydrogen peroxide in tumors. By injecting into the bloodstream it is possible to get much larger amounts of the vitamin to a tumor than is possible with oral supplements. However, other researchers studying the effects of vitamin C in cancers in mice saw no effect on tumor growth, and found that vitamin C interfered with many standard anti-cancer drugs.[61] The Cancer Treatment Centers of America (CTCA) in Zion, Illinois, is currently (2008) testing the safety of intravenous vitamin C in late-stage cancer patients for whom there is no other treatment option.[62]

Research since the 1960s has branched out further into nutrients besides niacin and vitamin C. David Horrobin did important work with essential fatty acids, which have played an increasingly important part in orthomolecular medicine. Patrick Kidd calls the omega-3 fatty acids docosahexanoic acid (DHA) and eicosapantenoic acid (EPA) truly "orthomolecular" in a 2007 review of their benefits.[63]

Although orthomolecular medicine is based on the idea that nutritional imbalances should be corrected before illness occurs, and consequently is not easily integrated into any single branch of medicine, its claims are particularly associated with psychiatry, in the field of orthomolecular psychiatry, and oncology, where Linus Pauling reported that Vitamin C could slow the progression of,[64] and even reverse,[65] cancer. As time went on Pauling came to believe that there was a deliberate and concerted effort to denigrate, distort and dissemble his efforts. Ewan Cameron the Scottish oncologist, who collaborated with Pauling, reluctantly came to agree as he believed to perceive mounting evidence to support Pauling's allegations of bad faith.[66]

Proponents of orthomolecular medicine claim that scientists associated with orthomolecular medicine had identified specific biochemical anomalies that account for many cases of bipolar disorder, schizophrenia, and some similar manifestations, such as, in one case, an previously undescribed copper toxicity disorder.

Most orthomolecular practitioners do not claim to be able to treat all diseases. As Abram Hoffer wrote in 1989: "Nor is orthomolecular treatment a replacement for standard treatment. A proportion of patients will require orthodox treatment, a proportion will do much better on orthomolecular treatment, and the rest will need a skillful blend of both."[74] For example, Hoffer admits that in his experience, acute and not chronic schizophrenia responds to niacin.[75]

Orthomolecular medicine is predicated on the premise that it is preferable to recognize and correct any possible anomalies in metabolism at an early stage, before they cause disease.[76] Orthomolecular medicine posits that many typical diets are insufficient for long term health; thus, orthomolecular medical diagnoses and treatment often focus on the use of nutrients such as vitamins, dietary minerals, proteins, antioxidants, amino acids, ω-3 fatty acids, ω-6 fatty acids, medium chain triglycerides, dietary fiber, and short and long chain fatty acids, although a wide range of other substances are used, such as lipotropes, systemic and digestive enzymes, other digestive factors, and prohormones. Abram Hoffer wrote a foreword to one edition of Weston Price's 1930 description of his travels and observations of the health and diet among "primitive" peoples who did not consume processed foods, and were spared the ravages of "degenerative" diseases.[77]

Orthomolecular nutrition and therapy attempts to provide optimal amounts of micronutrients. This is done after a diagnoses of the individual, which may involve a blood test, and a detailed personal history. Based on any deficiencies evident in the blood, an understanding of the patient's diet for the last six months or more, and the practitioners understanding of the symptoms exhibited, a prescription of nutrients, including megadoses of certain of them, will be given. Lifestyle changes, and diet changes, if these are indicated, will also be recommended. Modern orthomolecular practitioners also use a wide range of laboratory analyses, including those for amino acids, organic acids, vitamins and minerals, functional vitamin status, hormones, immunology, microbiology, digestive and gastrointestinal function. However, many of these tests are not employed by mainstream medicine for common diagnostic use.

Frequently supplementation with relatively large doses of vitamins is given, and the name megavitamin therapy is popularly associated with the area. Megavitamin therapy is the administration of large amounts of vitamins, often many times greater than the recommended dietary allowance (RDA). The nominal ratio of dose to RDA to qualify for the term 'megavitamin therapy' has been a matter of minor semantic debate.

A survey released in May 2004 by the National Center for Complementary and Alternative Medicine focused on who used complementary and alternative medicine (CAM), what was used, and why it was used in the United States by adults age 18 years and over during 2002. The survey reported uses in the previous twelve months that include orthomolecular related uses: Nonvitamin, nonmineral, natural products 18.9%, Diet-based therapies 3.5%, Megavitamin therapy 2.8%.[14] The survey did not include other popular related categories such as juicing, supplemental antioxidants, essential fatty acids, amino acids, enzymes and others.

Another recent CAM survey reported that 12% of liver disease patients used the antioxidant silymarin, more than 6% used megavitamins among others, and that "in all, 74% of patients reported using CAM in addition to the medications prescribed by their physician, but 26% did not inform their physician of their CAM use."[86] The use of high doses of vitamins is also common in people who have been diagnosed with cancer, although usage depends of the type of cancer and ranges from 26% to 35% among prostate cancer survivors up to 75% to 87% in breast cancer survivors.[15]

Orthomolecular medicine advocates claim that the methods of orthomolecular medicine overlap with those of both natural medicine and mainstream medicine. The International Society for Orthomolecular Medicine has conventionally-trained doctors among its members and authors, and the notable founders of orthomolecular medicine have all had professional degrees. The leading orthomolecular medicine website, Orthomolecular Medicine Online,[87] run by the Journal of Orthomolecular Medicine, discusses differences between orthomolecular medicine and mainstream medicine,[78][83]

On the other hand, the conventional view among mainstream medical physicians is that most orthomolecular therapies are insufficiently proven for clinical use, that the scientific foundations are weak, and that the studies that have been performed are too few and too open to disputed interpretation. The lack of serious testing of orthomolecular medicine has led to its practices being classed with other less plausible forms of alternative medicine and regarded as unscientific.[88][89][90] This form of alternative medicine has therefore been described as food faddism and even quackery, with critics arguing that it is based upon an "exaggerated belief in the effects of nutrition upon health and disease".[21][22][23] However, orthomolecular medicine is distinct from many other forms of alternative medicine, such as homeopathy, since its ideas are biologically-based and consistent with scientific laws, it does not involve magical thinking,[91] and it can generate testable hypotheses.[92]

Mainstream medicine also avoids the use of new treatments whose effects are unknown, instead favoring 'clinically proven' drugs tested using mainstream medical standards. Even with this standard of caution, it has been estimated that up to 20% of drugs may subsequently have unrecognized, serious adverse reactions, requiring the later addition of the "black box warning", or withdrawal from market.[96]

The skepticism about orthomolecular medicine comes in part because some of its proponents make claims more broad than those supported by scientific research, particularly claims that may contradict the results of clinical trials,[50][97] and rely instead on less reliable observational studies, clinical and anecdotal experience, single blinded controlled tests, and case histories. Proponents of orthomolecular medicine argue that, despite the extensive testing of pharmaceuticals, some medications are withdrawn after approval, due to serious adverse events, and the FDA regulatory methodology and relationship with the pharmaceutical industry has been criticized.[98]

Many mainstream medical institutions dismiss orthomolecular medicine entirely. The American Medical Association describes as "myths" the ideas that vitamin and mineral deficiencies are widespread, that the causes of most diseases are poor diets, or that most diseases can be prevented by nutritional supplements.[20] Similarly, the American Cancer Society comments that the current scientific evidence does not "support use of orthomolecular therapy for most of the conditions for which it is promoted". They stated some supplements have exhibited benefits for certain conditions, while a few have been confirmed to be harmful, and that the consumption of nutritious foods is the best recognized method to obtain vitamins, minerals, and nutrients crucial for good health.[16] In another example, an adviser on alternative medicine to the National Institutes of Health, stated that "Scientific research has found no benefit from orthomolecular therapy for any disease"[50] and a recent medical textbook also states that there is "no evidence that megavitamin or orthomolecular therapy is effective in treating any disease."[99]

Proponents of orthomolecular medicine counter that vitamins and nutrients are now used in conventional medicine as treatments for disease, such as megadose niacin and fish oil for dyslipidemias,[100][101][102] 6000-25,000 iu vitamin E per day[103][104] for the lipid disorder, abetalipoproteinemia, and megavitamin therapies for over a dozen amino acid metabolism disorders.[28] Current medical research on alternative medicine attempts to assess the evidence either for or against the variety of nutritional therapies currently offered, with a recent review in the Annals of Internal Medicine concluding that while some might be beneficial, others might be harmful or interfere with conventional therapy.[105]

Dietary supplements, such as those used in orthomolecular medicine, are less regulated than pharmaceuticals in the United States. Furthermore, a recent meta-analysis in JAMA suggested that supplementation with combinations of beta-carotene, vitamin A, and vitamin E may increase mortality, although with respect to beta-carotene this conclusion may be due to the known harmful effect in smokers.[106] An essential regulatory difference is that pharmaceuticals must be proven safe and effective to the satisfaction of the FDA before they can be marketed, whereas supplements must be proven unsafe before regulatory action can be taken.[107] A number of orthomolecular US supplements are available in pharmaceutical versions that are sometimes quite similar in strength and general content, or in other countries are pharmaceuticals. The US regulations also have provisions to recognize a general level of safety for established nutrients that can forgo new drug safety tests. Proponents of nutritional supplement use have argued that the lower level of regulation results in cost savings for American consumers, pointing to higher supplement prices in Europe, where some supplements are more tightly regulated or even unavailable.[108][109]

Aspects of orthomolecular therapy remain controversial among mainstream medical organizations and physicians, who consider many aspects to be lacking sufficient RCT-based evidence. In contrast, orthomolecular proponents argue that many mainstream nutritional studies, both recent and historical, provide investigational and clinical support for their treatments and recommendations.[110] They also argue that orthomolecular therapies are intrinsically less likely to cause dangerous side-effects or harm, since they utilize only chemicals that are normally present in the body.[3][111][112] Supporters claim that some aspects of orthomolecular medicine, and in particular the optimal nutrition subset, have support in mainstream scientific research in a variety of areas that do not claim to support orthomolecular doctrine, and in at least some cases, explicitly reject claims of orthomolecular proponents that nutritional supplements are desirable.[113]

Orthomolecular proponents, such as Robert Cathcart, who predicts that 120+ grams per day intravenous vitamin C should cure severe acute respiratory syndrome[114] and has used up to 250 grams IV vitamin C per day, have been criticized for not having any conventional medical trials of such intravenous vitamin C treatments.[115]

The relationship of mainstream medicine to orthomolecular proponents has often been adversarial; orthomolecular proponents, including Dr. Richard Kunin, argue that mainstream medical claimants confuse orthomolecular medicine with other, less science based modalities.[78] The American Academy of Pediatrics labelled orthomolecular medicine a "cult" in 1976, in response to claims that orthomolecular medicine could cure childhood psychoses and learning disorders.[118]

Vitamin E contains eight related chemicals, which are classed as either tocopherols or tocotrienols. These chemicals also exist as several stereoisomers.[126] In supplements these are usually present in stabilized ester forms, which are converted into the active form in the intestines.[127] Research has focussed on alpha-tocopherol, since this is the form preferentially taken up by the body and the most abundant form in tissues.[128] Alpha-tocopherol is also regarded in orthomolecular medicine as the form with greatest nutritional significance.[129] In supplements this is either a mixture of stereoisomers (all-rac-alpha-tocopherol), or the biological stereoisomer RRR-alpha-tocopherol.[126]

Initial hopes for the usefulness of vitamin E in orthomolecular medicine were based on epidemiological studies. These suggested that people who consumed more vitamin E had lower risks of chronic disease, such as coronary heart disease, and led to the idea that vitamin E supplementation could be beneficial.[130] However, these observational studies could not distinguish between whether the higher levels of vitamin E improved health themselves, or whether confounding variables were responsible - such as whether or not such people ate a more healthy diet or took more exercise.[131][132] To distinguish between these possibilities, many randomized controlled trials were performed. Meta-analysis of these controlled clinical trials have not shown any clear benefit from any form of alpha-tocopherol supplementation for preventing chronic disease.[133][134][135][126]

A meta-analysis published in 2005 found that more than 400 units alpha tocopherol per day was associated with an increase in all-cause mortality.[136] Furthermore, a significant relationship was seen between dose and all-cause mortality, with the risk of death increasing in line with the dose. This meta-analysis was criticized on a number of grounds, including that this increase in mortality could have been caused by alpha-tocopherol and beta carotene increasing the risk of lung cancer in heavy smokers.[137] A similar increase in mortality was seen in a 2007 meta-analysis[138] Here, no health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected when the high-quality and low-bias risk trials were examined separately. However, as the majority of these low-bias trials dealt with either elderly people, or people already suffering disease, these results may not apply to the general population.[139] This meta-analysis was later repeated and extended by the same authors, with the new analysis published by the Cochrane Collaboration; this also concluded that some vitamin E supplements could be harmful.[26]

Orthomolecular recommendations for vitamin E supplementation typically are based on a mixture of tocopheols and tocotrienols.[140] Forms of "vitamin E", which contain mixed R,R,R tocopherols and are also recommended by some orthomolecular practitioners.[141] These other forms of vitamin E have not been examined in as much detail as alpha-tocopherol and may have effects on health that are not produced by the alpha-tocopherol form alone.[142][129][143]

Conventional physicians express concern that megavitamin and orthomolecular therapies used solely as alternative treatments by other practitioners, if not successful, may create dangerous delays in obtaining conventional treatments, such as radiation and chemotherapy for cancer. For example, in a highly publicized Canadian controversy, the chemotherapy of a 13-year-old cancer patient, Tyrell Dueck, encountered a delay from legal actions, due to his parents' religious beliefs and interest in alternative treatments such as diet, herbs and vitamins.[144][145] Orthomolecular medical practitioners and orthomolecular oriented naturopaths have long expressed similar concerns about conventional medicine,[146] particularly with gut related and chronic diseases as well as viral diseases.[147][148][149][150] It is usually possible, however, to combine orthomolecular and conventional treatments.

Several orthomolecular related AIDS approaches such as multivitamins,[151] selenium[152] and amino acids[153] are used with reported improvements in patients. High dose vitamin C treatments have long been used clinically by some orthomolecular practitioners to treat AIDS patients.[154][155] However, in these situations, medical criticism arises when orthomolecular approaches are advocated as substitutes for, rather than complements to, current medical treatments such as antiretroviral drugs.[156]

An analysis of fifteen clinical trials of micronutrient therapies by the Cochrane Collaboration in 2005 found no conclusive evidence that such micronutrient approaches either reduce symptoms or mortality in HIV-infected adults who are not malnourished, but found evidence that giving vitamin A to infants with HIV is beneficial.[157] The protective effect of vitamin A in children was also seen in a further trial,[158] and it has been hypothesized that this effect might be due to vitamin A modulating the gut immune system.[159] Interestingly, no protection from vitamin A against infection was seen in healthy children.[160]

Some orthomolecular proponents claim that their findings are actively suppressed by mainstream medicine and the pharmaceutical industry. Abram Hoffer wrote that "there is no conspiracy led and directed by a single person or by a single organization ... [h]owever, there is a conspiracy led and directed by a large number of professionals and their associations who have a common aim to protect their hard-earned orthodoxy, no matter what the cost to their opponent colleagues or to their patients".[161] Mainstream medicine regards such claims of a conspiracy as unsubstantiated,[162][163] with a review in Journal of Clinical Oncology stating that the idea there is a conspiracy amongst physicians against unconventional and unproven treatments is a common theme in forms of alternative medicine such as megavitamin therapy.[164]

The actions of Matthias Rath in South Africa have come under particular scrutiny. Rath worked with Linus Pauling and served as Director of Cardiovascular Research at the Linus Pauling Institute until 1992. He has published several papers on orthomolecular medicine, most notably a review co-authored with Pauling,[165] with Abram Hoffer listing Rath as a notable contributor to the Journal of Orthomolecular Medicine.[166] However, the relationship between Rath and Pauling later broke down over a lawsuit on intellectual property rights.[167] Rath now promotes vitamins as a treatment for HIV infection, describing treatment with antiretroviral drugs as part of a global conspiracy serving the financial interests of the pharmaceutical industry.[156] In a lawsuit that found against Rath, the South African Medical Association blamed his vitamin products for several deaths,[168][169] the World Health Organization and two health agencies of the United Nations also described Rath's advertisements as "wrong and misleading" and "an irresponsible attack on ARV (antiretroviral) therapy."[170]

The Journal of Orthomolecular Medicine, founded in 1967 as the Journal of Schizophrenia, is the main publication of those involved in Orthomolecular Medicine. Abram Hoffer has written that "We had to create our own journals because it was impossible to obtain entry into the official journals of psychiatry and medicine. Before 1967 I had not found it difficult to publish reports in these journals, and by then I had about 150 articles and several books in the establishment press."[176]

^Ewan Cameron, Linus Pauling (1979). Cancer and vitamin C : a discussion of the nature, causes, prevention, and treatment of cancer with special reference to the value of vitamin C. New York: Norton. ISBN 0-393-50000-4.

^"Don't overlook niacin for treating cholesterol problems. If you can conquer or cope with the "niacin flush," this B vitamin can do wonders for cholesterol". Harv Heart Lett14 (8): 4–5. 2004. PMID 15100082.